! Project Summary/Abstract Sensori-neural hearing loss (SNHL) is caused by several factors, including excessive noise, drug/toxin exposure and genetic lesions. Taken together, hearing deficits represent the number one neurological disorder worldwide. Despite numerous past and ongoing clinical studies there is currently no effective therapeutic treatment for hearing loss and its associated decline in quality of life. At the cellular level hearing loss involves damage or loss of sensory hair cells and/or the afferent nerve fibers from the associated spiral ganglion neurons (SGNs). In many cases, the SGN cell bodies also degenerate over time and result in the inability to relay auditory signals to the brain. Thus, there is a need to develop safe and reliable pharmaceuticals, along with reliable drug delivery technologies to prevent and restore inner ear function. Numerous studies over the past three decades have revealed that two members of the neurotrophin family of growth factor proteins, neurotrophin-3 (NT3) and brain-derived neurotrophic factor (BDNF) are among the most critical trophic signals for development and maintenance of the SGNs. The weight of current experimental evidence, including animal efficacy studies, suggests that exogenous delivery of NT3 to the adult cochlea is a promising therapeutic avenue to mitigate or even reverse hearing loss. From extensive pre-clinical and clinical experience exploring the biology and therapeutic potential of the neurotrophins, it has been concluded that, for largely biophysical reasons, the NT3 protein (a small, highly basic molecule) is in itself a poor therapeutic entity. To circumvent limitations of neurotrophin proteins, Zebra Biologics, in collaboration with the Scripps Research Institute, has developed proprietary technology to generate agonist (i.e., activating) antibodies to several classes of cell surface receptors using function-based cellular assays that allow screening of very large (~1011) combinatorial antibody libraries. Zebra has now generated pools of candidate agonist antibodies to the NT3 receptor, TrkC. Zebra thus has the technical ability and experience to generate and bring into the clinic Trk agonist antibody therapies for neurodegenerative conditions, including hearing loss. The overall goal of this program is to identify, optimize, deliver and develop TrkC agonist antibodies into effective pharmaceuticals to treat hearing loss, subserving a critical unmet medical need. We propose submitting a Phase 1 STTR grant application addressing the following SAs: SA1: Select, Characterize and Optimize Fully Human TrkC Agonist Antibodies. Test agonist antibodies for intrinsic potencies (EC50), maximal responses (Emax) in the TrkC reporter cell line and compare to NT3. Determine the canonical signaling properties of selected agonists SA2: Select Agonist Antibodies That Activate TrkC in Mouse Neurons. Determine EC50, Emax and signaling properties of antibodies (selected in SA1) on cultured mouse SGNs !